Pharmaceutics
- Tablets, syrup, suppositories, IV (glass vial + argon, unstable in O2)
A: 80% OBA. Peak effect at 1 hour.
D: Vd 1L/kg, 20% protein bound. Penetrates BBB easily.
M: 100% hepatically metabolized. HER 0.3
- 95% conjugated with glucuronyl or sulfyl groups (saturatable)
- 5% via CYP2E1 \(\xrightarrow{\text{generates superoxide}}\)NAPQI\(\xrightarrow{+\text{glutathione}}\)inert. In overdose, conjugating pathway is saturated and glutathione exhausted \(\to\) NAPQI accumulation.
- Superoxide leads to hepatocellular injury (centrilobular necrosis)
- NAPQI uncouples oxidative phosphorylation \(\to\) histotoxic hypoxia, type B lactic acidosis
E: metabolites eliminated in urine.
- NAPQI also nephrotoxic \(\because\) depletes renal glutathione
MoA:
- Analgesia: Unclear mechanism. COX3 inhibition in CNS may contribute. Indirect endocannabinoid agonist. May directly inhibit transient receptor potential channels in nociceptors.
- Antipyresis: Inhibition of PGE2 in thalamus
- Hypotension: Mannitol excipient \(\to\) osmotic diuresis
N-acetylcysteine (antidote)
- Precursor to glutathione
- Replenishes glutathione stores \(\to\) inactivates NAPQI
- 150mg/kg load \(\to\) infusion to maintain adequate glutathione
- T1/2 = 5 hours